There is a pressing need for new classes of antitumor drugs, particularly drugs with activity against the common solid human tumors, most of which remain refractory to effective chemotherapy. This need argues for novel, rationally based approaches to drug development, combined with appropriate and effective models for evaluating antitumor activity. A fundamental event in neoplastic transformation, and one that distinguishes a normal cell from a tumor cell, is the inappropriate or faulty expression in a tumor cell of growth regulatory genes (oncogenes). A major function of oncogenes is to code for components of intracellular signal transduction pathways that medicate the processes that occur between binding growth factors to cell surface receptors and events in the cell nucleus leading to cell proliferation. The constitutive activation of these signal transduction pathways by oncogenes is a major factor leading to transformed cell growth. Thus, signal transduction pathways offer rational and novel biochemical targets for new anticancer drug development, and offers the promise of selective control of cancer cell growth by exploiting a basic biological difference between normal and tumor cells. The goals of the project are to 1) use novel chemical structures with activity against signal transduction pathways as candidate drugs for preclinical development and eventual clinical trial in cancer patients; 2) to conduct mechanistic studies of selected inhibitors of signal transduction; 3) to identify peptide inhibitors of the signal transducing enzyme phosphatidylinositol phospholipase C; and, 4) to identify clinically relevant mechanisms of drug resistance due to altered levels of intracellular signaling or reductive enzymes. The ultimate objective of the studies is to find novel and improved agents and strategies for treating cancer.